Imidazolic compounds and use thereof as alpha-2-adrenergic receptors

ABSTRACT

The invention provides compounds having the formula (1): 
                         
wherein R1 is hydrogen, fluoro or methoxyl, R1 being in position 2, 3, 4 or 5 of the aromatic carbocycle; R2 is hydrogen or methyl; R3 is hydrogen, methyl or ethyl; and their pharmaceutically acceptable acid addition salts, hydrates of their pharmaceutically acceptable acid addition salts as well as the isomers and the tautomers thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national phase of International Appin. No.PCT/FR03/01476, filed May 15, 2003, and claims priority under 35 U.S.C.§ 119(a)–(d) of French Patent Application No. 02/06026, filed May 16,2002, said applications being incorporated by reference herein in theirentireties and relied upon.

The present invention relates to new imidazolic compounds. Thederivatives according to the invention interact selectively with preand/or post-synaptic alpha-2 type adrenergic receptors (J. Neurochem.2001, 78, 685–93) on which they behave as partial agonists, antagonistsor reverse agonists. As such, the compounds according to the inventionare therefore potentially useful in the treatment of diseases orconditions susceptible to adrenergic regulation controlled by alpha-2adrenergic receptors. The list of diseases considered as susceptible tosuch regulation is excessively long. However, the scope of the presentinvention is restricted to the treatment of neurodegenerative diseasesand the treatment of the progression thereof (Psychopharmacology 1996,123(3), 239–49; Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1999,23(7), 1237–46; U.S. Pat. No. 5,663,167; FR 2789681; WO 9835670; WO9806393; WO 9500145; WO 9413285; WO 9118886), particularly the treatmentof Alzheimer's disease or the treatment of the progression thereof (U.S.Pat. No. 5,281,607; FR 2795727; WO 9501791; WO 9415603).

Alzheimer's disease is the most widespread progressive degenerativedisease in the elderly population. It is estimated that over 15 millionpeople are affected (New Engl. J. Med. 1999, 341(22), 1670–79; DrugBenefit Trends 2001, 13/7, 27–40). Acetylcholinesterase inhibitors (e.g.tacrine, donepezil, rivastigmine and galantamine) represent, at thepresent time, the only symptomatic treatment of this disease. However,the therapeutic benefits obtained are modest at the very mode (Drugs2001, 61/1, 41–52). Since effective therapeutic strategies againstAlzheimer's disease are limited (Curr. Opin. Invest. Drugs 2001, 2(5),645–56), the discovery of new treatments using molecules with adifferent mode of action to that of the molecules currently available inclinical practice and capable of treating or delaying the progression ofthe disease is therefore highly desirable.

It has been demonstrated, in vitro and on animals, that a substanceactivating the noradrenergic system may, firstly, inhibit theprogression of neuronal degeneration (J. Neurophysiol. 1998, 79(6),2941–63; Pharmacol. Biochem. Behav. 1997, 56(4), 649–55; J. Cereb. BloodFlow Metabolism 1990, 10(6), 885–94) and, secondly, stimulate neuronalgrowth (J. Comp. Neurol. 1974, 155(1), 15–42; Neuroscience 1979, 4(11),1569–82; Neuroreport 1991, 2, 528–8). As a result, compounds withpartial agonistic, antagonistic or reverse antagonistic properties onalpha-2 adrenergic receptors, particularly on pre-synaptic alpha-2receptors, may be useful in the treatment of neurodegenerative diseases.In view of the therapeutic potential of compounds with partialagonistic, antagonistic or reverse antagonistic properties for alpha-2adrenergic receptors, the discovery of new structures having suchproperties is highly desirable. As such, the applicant discovered thatnew imidazolic derivatives interact selectively with alpha-2 subtypeadrenergic receptors on which they behave as partial agonists,antagonists or reverse agonists.

Numerous pre and/or post-synaptic antagonists and/or partial agonists ofalpha-2 adrenergic receptors are known and described in the literature.Although the compounds in questions belong to different chemical classes(Idrugs 2001, 4(6), 662–76), some comprise a common 1H-imidazole typestructural unit in their chemical structure. For example, the latterinclude compounds such as:

-   -   4-(1-indanylalkyl)-(WO 1051472);    -   4-(benzothienyl)-(WO 9951593);    -   dihydro-indole-(FR 2735776);    -   dihydro-indenyl-(EP 247764);    -   4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-(WO 9500492);    -   4(5)-(2-ethyl-2,3-dihydro-2-silainden-2-yl)-(Eur. J. Med. Chem.        1996, 31(9), 725–9;    -   thieno[3,4-c]pyrroles (EP 599697);    -   4-(2-aryl- and -cycloalkyl-3,3,3-trifluoropropyl)-(EP 486385);    -   4-subsitute-imidazole (J. Med. Chem. 1992, 35(4), 750–5);    -   4(5)-(2,2-diphenylethyl)-(Eur. J. Med. Chem. 1990, 25(7),        557–68);    -   imidazole derivative (GB 2225782; EP 183492 and WO 9313074);    -   4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-(WO 9500492).

Of the compounds mentioned above, some only comprise relatively minimalstructural differences. The most similar state of the art is representedby polycyclic indanylimidazole type compounds, claimed in the patent WO0185698, complying with formula a below:

wherein, among others:

-   -   A may form, with the two carbon atoms whereby it is attached, a        3-chain carbon-containing mono-cycle;    -   m may be 0 or 1;    -   R2 may be a (C1–6)alkyl group    -   t may be 0 or 1;    -   t is 1 and R1 may be a halogen or a (C1–6)alkyloxy group;    -   R3 may be a hydrogen, OH, ═O, (C1–6)alkyl or (C1–6)alkyloxy.

Therefore, the compounds represented above and the compounds accordingto the present invention are differentiated in the nature of thesubstituent in position 4 of the imidazole group, particularly by thepresence of a 6-spiro-cyclopropane structural unit in the compoundsaccording to the invention. Many structures comprising a 1H-imidazolegroup substituted in position 4 are already known for these alpha-2adrenergic properties (see above). However, surprisingly, it appearsthat the substituent6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl givesthe compounds according to the invention a very specific pharmacologicalprofile.

In fact, we have demonstrated, in vitro:

-   -   an affinity of the compounds according to the invention with        respect to the human alpha-2A subtype,    -   antagonistic or reverse agonistic properties of the compounds        according to the invention on alpha-2A receptors.

In addition, we have demonstrated, in vivo, that the products accordingto the invention are capable of inhibiting the effect of scopolamine ina memory deficiency test. This test is considered as a representativeanimal model of the memory disorders arising in the course ofAlzheimer's disease (Psychopharmacology 1992, 106, 26–30; Eur. J. Clin.Invest. 1998, 28, 944–9; Exp. Neurol. 2000, 163, 495–529). The compoundsaccording to the invention, having such an activity profile, aretherefore potentially useful for the treatment of diseases or disorderssusceptible to the action of partial agonists, antagonists or reverseagonists of alpha-2 adrenergic receptors, particularly for the treatmentof neurodegenerative diseases for which a significant therapeuticrequirement exists.

Finally, the preparation method of the compounds according to theinvention is different that of the compounds claimed in the patient WO0185698.

More specifically, the present invention relates to new4-(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazolederivatives which, in their basic form, comply with the general formula1:

wherein:

-   -   R1 represents a hydrogen atom, a fluorine atom or a methoxyl        group (OCH₃), the substituent R1 on the aromatic carbocycle        possibly occupying the position 2, 3, 4 or 5;    -   R2 represents a hydrogen atom or a methyl group;    -   R3 represents a hydrogen atom, a methyl group or an ethyl group;

their addition salts and, if applicable, addition salt hydrates withpharmaceutically acceptable mineral acids or organic acids along withtheir tautomeric forms, enantiomers and enantiomer mixtures andstereoisomers, pure or in racemic mixtures or not.

In a particular embodiment of the invention, the compounds according toformula 1 wherein:

-   -   R1 and R2 have the same significance as above;    -   R3 represents a methyl group or an ethyl group;

the preferential stereoisomers of the products according to theinvention are those wherein the R3 and 1H-imidazole substituents occupyeither anti-periplanar positions or syn-periplanar positions withreference to the plane defined by the cyclopropanic nucleus.

The term anti-periplanar is used by the inventors to refer to therelative configurations of the molecules 1 for which the R3 and1H-imidazole substituents are located on either side of the planedefined by the cyclopropanic nucleus. The term syn-periplanar is used bythe inventors to refer to the relative configurations of the molecules 1for which the R3 and 1H-imidazole substituents are located on the sameside of the plane defined by the cyclopropanic nucleus.

The compounds according to the general formula 1 may exist in severaltautomeric forms. Such tautomeric forms, although they are notexplicitly reported in the present application to simplify the graphicrepresentation of the developed formulas, are nevertheless included inthe scope of the invention. The compounds according to the inventioncomprise several asymmetrical carbon atoms in their structure. For thisreason, they exist in the form of enantiomers and diastereoisomers. Theinvention relates equally well to each pure stereoisomer, i.e.associated with less than 5% of another stereoisomer or a mixture ofother stereoisomers, and mixtures of one or more stereoisomers in allproportions. Therefore, the compounds according to the invention may beused as pure stereoisomers or racemic or non-racemic stereoisomermixtures.

Finally, the invention relates to the preparation method of derivativesaccording to general formula 1.

The derivatives according to general formula 1 may be obtained using themethod described in the reaction diagram below.

The preparation of the compounds according to the invention uses, as rawmaterials, the suitably substituted derivatives according to formula I,the synthesis method of which is described in the French patentapplication No. 0201839. A cyclopropanation reaction of the double bond,produced using a similar technique to that reported in Angew. Chem. Int.Ed. 2000, 39(24), 4539–42, results in the spiro derivative according toformula II. The ester function of the compound according to formula IIis then reduced into the alcohol according to formula II by means oflithium borohydride in tetrahydrofuran according to a conventionalorganic chemistry method. The primary alcohol III is oxidised into thealdehyde according to formula IV by means of sulphur trioxide pyridinecomplex. The aldehyde IV is converted into the imidazole expected fromformula 1, either in one step according to the method described inHeterocycles 1994, 39(1), 139–53; or via tosyl-formylamine according toformula V according to the method reported in Recl. Trav. Chim. Pays Bas1979, 98(5), 258–62.

The invention also relates to pharmaceutical formulations containing, asthe active ingredient, at least one of the derivatives according togeneral formula 1 or one of its salts or hydrates of its salts incombination with one or more inert substrates or other pharmaceuticallyacceptable vehicles.

The pharmaceutical formulations according to the invention may be, forexample, formulations for oral, nasal, sublingual, rectal or parenteraladministration. Examples of formulations for oral administration includetablets, capsules, granules, powders and solutions or oral suspensions.

The formulations suitable for the selected form of administration areknown and described for example, in: Remington, The Science and Practiceof Pharmacy, 19^(th) edition, 1995, Mack Publishing Company.

The effective dose of a compound according to the invention variesaccording to numerous parameters such as, for example, theadministration route selected, the weight, age, sex, state ofprogression of the disease to be treated and the susceptibility of thesubject to be treated. As a result, the optimal dosage should bedetermined, according to the parameters deemed relevant, by thespecialist in the field. Although the effective doses of a compoundaccording to the invention may vary in wide proportions, the daily dosescould range between 0.01 mg and 100 mg per kg of body weight of thesubject to be treated. However, a daily dose of a compound according tothe invention between 0.10 mg and 50 mg per kg of body weight of thesubject to be treated is preferred.

The pharmaceutical formulations according to the invention are useful inthe treatment of neurodegenerative diseases.

EXAMPLES

The following examples illustrate the invention, but do not limit it inany way.

In the examples and reference examples below:

(i) the progress of the reactions is monitored by means of thin layerchromatography (TLC) and, as a result, the reaction times are onlymentioned as an indication;

(ii) different crystalline forms may give different melting points, themelting points reported in the present application are those of theproducts prepared according to the method described and are notcorrected;

(iii) the structure of the products obtained according to the inventionis confirmed by the nuclear magnetic resonance (NMR) and infrared (IR)spectra and centesimal analysis, the purity of the end products isverified by TLC, the enantiomeric purity of the reaction intermediatesand the end products is determined by chiral phase HPLC;

(iv) the NMR spectra are recorded in the solvent specified. The chemicalshifts (δ) are expressed in parts per million (ppm) with reference totetramethylsilane. The multiplicity of the signals is specified by: s,singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; l, large.

(v) the different symbols of the units have their usual meaning: μg(microgram); mg (milligram); g (gram); ml (millilitre); mV (millivolt);° C. (degrees Celsius); mmole (millimole); nmole (nanomole); cm(centimetre); nm (nanometre), min (minute); ms (millisecond), Hz(hertz); [α] (specific rotatory power measured at 589 nm, 25° C. and atthe concentration c, in the present invention the dimension deg.cm².g⁻¹is always understood); pressures are given in millibar (mb);

(vi) the abbreviations have the following meaning: F (melting point); Eb(boiling point); AUC (area under the curve);

(vii) the term “ambient temperature” refers to a temperature between 20°C. and 25° C.

Example 1(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-ethylcarboxylate II-1

In the solution of 24.5 g (0.124 mole) of 2,4,6-trichlorophenol and 300ml of dichloromethane under stirring and in nitrogen at −40° C., 113 ml(0.124 mole) of a toluene ZnEt₂ (1.1M) solution is added drop by drop.After 15 minutes of stirring at −40° C., 10 ml (0.124 mole) ofdiiodomethane is added and kept under stirring for 15 minutes beforeadding 6-methylene-1a,6-dihydro-1H-cyclopropa[a]inden-6a-ethylcarboxylate I-1, 13.22 g (0.062 mole). The suspension obtained is keptunder stirring at ambient temperature overnight. After addingdichloromethane until completely dissolved, the solution is washed twicewith 1N HCl followed by Na₂SO₄ and 0.5N NaOH (twice) and salinesolution. The organic phase is dried on MgSO₄, filtered and the solventis eliminated in a vacuum. The oil obtained is purified by silica gelchromatography using cyclohexane with 2% ethyl acetate as the eluent.

Yield: 89.8% C₁₅H₁₆O₂: 228.29 ¹H NMR (CDCl₃): 0.88 (m, 1H); 0.92 (m,2H); 1.23 (t, 3H); 1.29 (m, 1H); 1.81 (dd, 1H); 2.35 (m, 1H); 3.17 (dd,1H); 4.10 (d, 2H); 6.56 (m, 1H); 7.07 (m, 2H); 7.25 (m, 1H). ¹³C NMR(CDCl₃): 14.15; 14.47; 17.16; 27.47; 29.21; 34.09; 34.16; 60.22; 118.97;122.76; 125.40; 126.43; 142.46; 147.45; 171.84.

Example 2(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-methanolIII-1

The suspension of 13 g (0.234 mole) of KBH₄, 10.5 g (0.239 mole) of LiCland 100 ml of anhydrous THF is kept under stirring at ambienttemperature for 1 hour. To this suspension, the solution of 12.71 g(0.056 mole) of(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-ethylcarboxylate II-1 in 70 ml of anhydrous THF is added drop by drop andthen reflux-heated under stirring for 4 hours. The suspension isvacuum-concentrated and the residue is treated with water. The productis extracted twice with ethyl acetate. The organic phase is washed withsaline solution, dried on MgSO₄, filtered and vacuum-concentrated. Theunprocessed oil is purified by silica gel chromatography usingcyclohexane with 20% ethyl acetate as the eluent.

Yield: 85% C₁₃H₁₄O: 186.25 ¹H NMR (CDCl₃): 0.64 (t, 1H); 0.96 (m, 2H);1.17 (m, 2H); 1.25 (t, 1H, exchangeable with D₂O); 1.54 (m, 1H); 2.49(q, 1H); 3.56 (dd, 1H, (d, after exchange with D₂O)); 3.74 (dd, 1H, (d,after exchange with D₂O)); 6.58 (m, 1H); 7.06 (m, 2H); 7.25 (m, 1H).

Example 3(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-carboxaldehydeIV-1

In the solution of 1.2 g (6.44 mmoles) of(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-methanolIII-1 and 6 ml of anhydrous DMSO, 2.7 ml (19.4 mmoles) of triethylamineis added. The mixture obtained is placed under stirring on a chilledwater bath and pyridine-SO₃ complex is added in 3.1 g (19.4 mmoles)fractions. After 4 hours of stirring at ambient temperature, thesolution is poured into chilled water. The product is extracted twicewith ethyl acetate. The organic phase is washed with an aqueous citricacid solution and then with saline solution. After drying on MgSO₄ andfiltration, the solvent is eliminated at reduced pressure. The residualoil obtained is used without any other purification in the subsequentstep.

C₁₃H₁₂O: 184.23 ¹H NMR (CDCl₃): 0.97–1.03 (m, 2H); 1.15 (t, 1H); 1.23(m, 1H); 2.01 (dd, 1H); 2.37 (m, 1H); 3.15 (dd, 1H); 6.62 (d, 1H); 7.12(m, 2H); 7.26 (t, 1H); 9.26 (s, 1H).

Example 44-(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole1-1

In the suspension of 1.18 g (6.4 mmoles) of(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-carboxaldehydeIV-1, 1.25 g (6.4 mmoles) of paratolylsufonylmethyl isocyanide and 15 mlof absolute ethanol under stirring at ambient temperature, 40 mg ofsodium cyanide is added. After 1 hour of stirring at ambienttemperature, the majority of the ethanol is eliminated at reducedpressure. To the residue, 20 ml of methanol ammonia (4N) solution isadded and the solution obtained is maintained at 90° C. for 16 hours.After returning to ambient temperature, the brown solution obtained isheated to dryness at reduced pressure. The residue is taken up withethyl acetate and the insolubles are filtered. The mother liquors areextracted twice with 1N hydrochloric acid. The acidic aqueous phase arewashed with ether and then alkalinised. The product is extracted twicewith ethyl acetate. The organic phases are washed with saline solution,dried on MgSO₄, filtered and the solvent is eliminated at reducedpressure. The residue is purified by silica chromatography usingchloroform with 3% methanol as the eluent.

Yield: 28.8% C₁₅H₁₄N₂: 222.28 Fumarate of compound in title, F: 218–220°C. Elementary analysis, C₁₉H₁₈N₂O₄: 338.36 Calculated: C, 67.45%; H,5.36%; N, 8.28%. Found: C, 67.17%; H, 5.36%; N, 8.15%. ¹H NMR (DMSOd₆):0.61 (t, 1H); 0.79 (m, 2H); 0.94 (m, 1H); 1.09 (m, 1H); 1.46 (dd, 1H);2.71 (dd, 1H); 6.62 (s, 2H); 6.68 (m, 1H); 6.90 (s, 1H); 7.06 (m, 2H);7.28 (m, 1H); 7.63 (s, 1H).

The compounds according to formula 1-1 are split by liquidchromatography on CHIRALCEL OD substrate.

Example 5(+)-4-(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole(+)-(1-1)

Fumarate of compound in title, F: 168–170° C. [α]²⁵ _(D)=+50.5°(c=0.334, CH₃OH) Elementary analysis, C₁₉H₁₈N₂O₄: 338.36 Calculated: C,67.45%; H, 5.36%; N, 8.28%. Found: C, 67.24%; H, 5.39%; N, 8.12%.

Example 6(−)-4-(6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole(−)-(1-1)

Fumarate of compound in title, F: 170–172° C. [α]²⁵ _(D)=−47.75°(c=0.295, CH₃OH) Elementary analysis, C₁₉H₁₈N₂O₄: 338.36 Calculated: C,67.45%; H, 5.36%; N, 8.28%. Found: C, 67.23%; H, 5.36%; N, 8.16%.

Example 74-(1-exo-methyl-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole1-2

Using1-exo-methyl-6-methylene-1a,6-dihydro-1H-cyclopropa[a]inden-6a-ethylcarboxylate I-2 as the starting product and following the proceduredescribed in examples 1–4, the compound in the title is obtained.

Fumarate of compound in title, F: 203–205° C. Elementary analysis,C₂₀H₂₀N₂O₄: 352.39 Calculated: C, 68.17%; H, 5.72%; N, 7.95%. Found: C,68.69%; H, 5.90%; N, 8.07%. ¹H NMR (DMSOd₆): 0.57 (m, 1H); 0.65 (m, 1H);0.88 (s, 3H); 0.92 (m, 1H); 1.28 (m, 1H); 2.54 (d, 1H, J=1.6 Hz); 6.61(s, 2H); 6.63 (m, 1H); 6.68 (s, 1H); 7.04 (m, 2H); 7.28 (m, 1H); 7.66(s, 1H).

Example 84-(1-endo-ethyl-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole1-3

Using(1-endo-ethyl-6-methylene-1a,6-dihydro-1H-cyclopropa[a]inden-6a-ethylcarboxylate I-3, itself obtained from (Z)-2-(1-butenyl)-benzoic acid (RN129780-54-7), as the starting product and following the proceduredescribed in examples 1–4, the compound in the title is obtained.

Fumarate of compound in title, F: 179–181° C. Elementary analysis,C₂₁H₂₂N₂O₄: 366.42 Calculated: C, 68.84%; H, 6.05%; N, 7.64%. Found: C,68.36%; H, 5.99%; N, 7.63%. ¹H NMR (D₂O): 0.62 (m, 1H); 0.86 (t, 3H);0.95 (m, 2H); 1.14 (m, 1H); 1.20 (m, 1H); 1.38 (m, 1H); 1.74 (m, 1H);3.03 (d, 1H, J=8.8 Hz); 6.66 (s, 2H); 6.75 (m, 1H); 7.21 (m, 2H); 7.31(s, 1H); 7.39 (m, 1H); 8.56 (s, 1H)

Example 94-(1a-methyl-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole1-4

Using(1a-methyl-6-methylene-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-ethylcarboxylate I-4, itself obtained from 2-isopropenyl benzoic acid (RN3609-46-9), as the starting product and following the proceduredescribed in examples 1–4, the compound in the title is obtained.

Example 104-(4-fluoro-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole1-5

Using(4-fluoro-6-methylene-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-ethylcarboxylate I-5 as the starting product and following the proceduredescribed in examples 1–4, the compound in the title is obtained.

Fumarate of compound in title, F: 214–216° C. Elementary analysis,C₁₉H₁₇N₂FO₄: 356.35 Calculated: C, 64.04%; H, 4.81%; N, 7.86%. Found: C,63.87%; H, 4.88%; N, 7.81%. ¹H NMR (DMSOd₆): 0.60 (t, 1H); 0.83 (m, 2H);0.98 (m, 1H); 1.09 (m, 1H); 1.42 (dd, 1H); 2.68 (dd, 1H); 6.56 (d, 1H);6.66 (s, 2H); 6.83 (m, 1H); 6.88 (s, 1H); 7.27 (m, 1H); 7.59 (m, 1H).

The compounds according to formula 1 and their therapeuticallyacceptable salts offer properties of pharmacological interest.

The results of the tests are given in the table below:

Scopolamine memory deficiency % amplitude Affinity Intrinsic of effect(pKi) activity (dose, mg/kg Compound Alpha-2A % stimulated i.p.) 1—1 9.5 +14 +122 (2.5)  (—) - — +100 — adrenaline Donepezil — —  +67 (0.16)Bonds with alpha-2 adrenergic receptors

The C6 cell membranes continuously expressing the human alpha-2Areceptor are prepared in Tris-HCl (pH=7.6). The bond tests are conductedwith 2 nM [₃H]RX 821002. The incubation medium consists of 0.4 ml ofcell membranes (10 μg of proteins), 0.05 ml of radioligand and 0.05 mlof test product or phentolamine (10 μM) to determine the non-specificbond. The reaction is stopped after 30 minutes of incubation at 25° C.by adding 3 ml of Tris-HCl, 50 mM (pH=7.6), cold, followed by filtrationon Whatman filters, GF/B using a Brandel. The Ki values are calculatedaccording to the equation Ki=IC₅₀/(1+C/Kd) where C is the concentrationand Kd the dissociation constant, pKi=−logKi. Under these conditions,the compounds according to the invention appear to have a strongaffinity for human alpha-2A adrenergic subtype receptors.

Measurement of Alpha-2 Adrenergic Receptor Activation

The GTPγS responses are produced on membrane preparations in 20 mM HEPES(pH=7.4) with 30 μM of GDP, 100 mM of NaCl, 3 mM of MgCl₂ and 0.2 mM ofascorbic acid. The maximum GTPγS stimulation is determined in thepresence of 10 mM of (−)-adrenaline and calculated with respect to thebasal GTPγS response. The results are expressed with reference toadrenaline or RX 811059. Under these conditions, the compounds accordingto the invention are distinguished from the majority of the compoundsaccording to the prior art in that they behave more like reverseagonists on human alpha-2A adrenergic receptors (see table above).

Scopolamine-induced Memory Deficiency Test.

Scopolamine has amnesiac properties in animals and humans. In this way,its administration to healthy humans induces certain symptoms similar tothose observed in Alzheimer's disease. Therefore, thescopolamine-induced memory deficiency is used as an experimentalpharmacological model of the memory disorders observed in the course ofthis condition. Scopolamine reduces acquisition, memorisation and recallcapacities in a passive avoidance test in rats. It consists of measuringthe hesitancy, after learning, shown by an animal to enter a darkcompartment in which it receives a low-intensity electric shock. Theadministration of scopolamine does away with this hesitancy and thecompounds studied inhibit the effect of scopolamine. The experimentalprotocol used is described in Psychopharmacol. 1992, 106, 26–30.

The compounds according to the invention show a high activity (see tableabove). The amplitude of the effect obtained with the compoundsaccording to the invention is greater than that, for example, ofdonezepil, an acetylcholinesterase inhibitor used in clinical practicefor the treatment of Alzheimer's disease (Chem. Rec. 2001, 1(1), 63–73).Therefore, the compounds according to the invention are capable ofeffectively inhibiting the memory deficiency induced by scopolamine.

Therefore, the results of the tests demonstrate that the compoundsaccording to the formula 1:

-   -   have a strong affinity for human alpha-2A subtype adrenergic        receptors;    -   generally behave as partial agonists or antagonists or reverse        agonists on human alpha-2A adrenergic receptors;

are active, in vivo, in an animal model considered to be representativeof the memory disorders observed in the course of Alzheimer's disease.

For this reason, the compounds according to their invention and theirtherapeutically acceptable salts are potentially useful as medicinalproducts, particularly in the treatment of some progressiveneurodegenerative diseases, such as Alzheimer's disease, for example.

The compounds according to the invention may be administered by theoral, nasal, sublingual, rectal or parenteral route. As a non-limitativeexample of a formulation, a preparation of the compounds according tothe invention is given below. The ingredients and other therapeuticallyacceptable substances may be introduced in other proportions withoutmodifying the scope of the invention. The terms ‘active ingredient’ usedin the formulation example below refer to a compound according toformula 1 or an addition salt or, if applicable, an addition salt of thecompound according to formula 1 with a pharmaceutically acceptablemineral acid or organic acid.

Example of Pharmaceutical Formulation

Preparation formula for 1000 tablets each containing 10 mg of activeingredient consisting of at least one imidazolic compound according tothe invention:

Active ingredient  10 g Lactose 100 g Cornstarch  10 g Magnesiumstearate  3 g Talc  3 g

1. A compound having the formula (1):

wherein: R1 represents a hydrogen atom, a fluorine atom or a methoxylgroup (OCH₃), the substituent R1 on the aromatic carbocycle occupyingthe position 2, 3, 4 or 5; R2 represents a hydrogen atom or a methylgroup; R3 represents a hydrogen atom, a methyl group or an ethyl group;or an addition salt or, addition salt hydrate thereof with apharmaceutically acceptable mineral acid or organic acid, orenantiomers, diastereoisomers or tautomer thereof.
 2. A compoundaccording to claim 1, which is selected from the group consisting of:4-(6-spiro-1′-Cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(2-fluoro-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(3-fluoro-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(4-fluoro-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(5-fluoro-6-spiro-1t-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(1-exo-methyl-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(1-exo-methyl-2-fluoro-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(1-exo-methyl-3-fluoro-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(1-exo-methyl-4-fluoro-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(1-exo-methyl-5-fluoro-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole;4-(1-endo-ethyl-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cycloprop[a]inden-6a-yl)-1H-imidazole; and4-(1a-methyl-6-spiro-1′-cyclopropane-1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole; and the addition salts and addition salt hydrates thereofwith pharmaceutically acceptable mineral acids or organic acids, and theenantiomers, diastereoisomers and tautomers thereof.
 3. A process forthe preparation of a compound of formula 1according to claim 1, saidprocess comprising reacting a synthetic intermediate having formula (I):

wherein R1, R2and R3have the same significance as in formula (1), withdichloromethane in the presence of zinc diethyl and phenol andconverting the ester function of the compound formed into a 1H-imidazolegroup to afford the corresponding compound of formula (1) wherein R1,R2and R3have the same significance as in formula (1).
 4. A compoundaccording to claim 1, wherein the R3and 1H-imidazole substituents occupysyn-periplanar positions with reference to the plane defined by thecyclopropanic nucleus, R1and R2have the same significance as in formula(1) and R3is a methyl group (OH₃) or an ethyl group (CH₂CH₃).
 5. Acompound according to claim 1, wherein the R3and 1H-imidazolesubstituents occupy anti-periplanar positions with reference to theplane defined by the cyclopropanic nucleus, R1and R2have the samesignificance as in formula (1) and R3is a methyl group (CH₃) or an ethylgroup (CH₂CH₃).
 6. A compound having the formula (1), according to claim1, which is the levogyral enantiomer or the dextrogyral enantiomer of acompound of formula (1).
 7. A pharmaceutical formulation comprising, asthe active ingredient, at least one compound or salt or salt hydratethereof or enantiomers, diastereoisomers or tautomer thereof accordingto claim 1, associated with an inert substrate or other pharmaceuticallyacceptable vehicles.
 8. A compound having the formula (1) according toclaim 2, which is the levogyral enantiomer or the dextrogyral enantiomerof a compound of formula (1).
 9. A compound having the formula (1)according to claim 4, which is the levogyral enantiomer or thedextrogyral enantiomer of a compound of formula (1).
 10. A compoundhaving the formula (1) according to claim 5, which is the levogyralenantiomer or the dextrogyral enantiomer of a compound of formula (1).11. A pharmaceutical formulation comprising, as the active ingredient,at least one compound of formula (1) or salt or salt hydrate thereof orenantiomer or diastereoisomer or tautomer thereof according to claim 2,associated with an inert substrate or other pharmaceutically acceptablevehicles.
 12. A pharmaceutical formulation comprising, as the activeingredient, at least one compound according to claim 4, associated withan inert substrate or other pharmaceutically acceptable vehicles.
 13. Apharmaceutical formulation comprising, as the active ingredient, atleast one compound according to claim 5, associated with an inertsubstrate or other pharmaceutically acceptable vehicles.
 14. Apharmaceutical formulation comprising, as the active ingredient, atleast one compound according to claim 6, associated with an inertsubstrate or other pharmaceutically acceptable vehicles.